Somatic mutations in myeloid cell leukemia‑1 contribute to the pathogenesis of glioma by prolonging its half‑life

Lv,Xiupeng; Tan,Guang; Yao,Yiqun; Lv,Li; Deng,Xiaoqin; Dong,Lei; Li,Shuang; Li,Linlin; Xu,Yinghui

doi:10.3892/mmr.2015.3493

Somatic mutations in myeloid cell leukemia‑1 contribute to the pathogenesis of glioma by prolonging its half‑life

Authors:
- Xiupeng Lv
- Guang Tan
- Yiqun Yao
- Li Lv
- Xiaoqin Deng
- Lei Dong
- Shuang Li
- Linlin Li
- Yinghui Xu
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Affiliations: Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: March 13, 2015 https://doi.org/10.3892/mmr.2015.3493
Pages: 1265-1271

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Abstract

The identification of mutated genes in glioblastoma multiforme (GBM) is an essential step towards improving current understanding of the molecular mechanism underlying the disease and establishing novel targets for diagnostic and therapeutic purposes. The present study used direct sequencing to screen 20 malignancy‑associated genes, which have either been well described in the literature or observed multiple times in human cancer sequencing, in cancerous and normal control tissue samples from 20 patients with histologically confirmed GBM. The investigation identified five somatic non‑synonymous coding mutations in four candidate genes, with two located in the proline, glutamic acid, serine, threonine‑rich region of myeloid cell leukemia sequence 1 (Mcl)‑1, (D155G and L174S). The sample pool was then expanded by sequencing Mcl‑1 in a further 43 patients with GBM and another somatic mutation in the same region, D155H, was identified. The subsequent functional investigation confirmed that these somatic mutations affected the degradation of Mcl‑1, and the growth of glioma cells transfected with mutant plasmids was significantly accelerated compared with cells overexpressing wild‑type Mcl‑1. The mutational profiling of GBM in the present study revealed for the first time, to the best of our knowledge, several mutations in Mcl‑1, and identified this gene as a novel therapeutic target for the treatment of GBM.

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1	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
2	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
3	Hemminki K and Li X: Familial risks in nervous system tumors. Cancer Epidemiol Biomarkers Prev. 12:1137–1142. 2003.PubMed/NCBI
4	Scheurer ME, Etzel CJ, Liu M, El-Zein R, Airewele GE, Malmer B, Aldape KD, Weinberg JS, Yung WK and Bondy Ml: Aggregation of cancer in first-degree relatives of patients with glioma. Cancer Epidemiol Biomarkers Prev. 16:2491–2495. 2007. View Article : Google Scholar : PubMed/NCBI
5	Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061–1068. 2008. View Article : Google Scholar : PubMed/NCBI
6	Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI
7	Vogelstein B and Kinzler KW: Cancer genes and the pathways they control. Nat Med. 10:789–799. 2004. View Article : Google Scholar : PubMed/NCBI
8	Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, et al: Patterns of somatic mutation in human cancer genomes. Nature. 446:153–158. 2007. View Article : Google Scholar : PubMed/NCBI
9	Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, et al: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 321:1801–1806. 2008. View Article : Google Scholar : PubMed/NCBI
10	Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, et al: The consensus coding sequences of human breast and colorectal cancers. Science. 314:268–274. 2006. View Article : Google Scholar : PubMed/NCBI
11	Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, et al: The genomic landscapes of human breast and colorectal cancers. Science. 318:1108–1113. 2007. View Article : Google Scholar : PubMed/NCBI
12	Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A and Hemminki K: Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark and Finland. N Engl J Med. 343:78–85. 2000. View Article : Google Scholar : PubMed/NCBI
13	Bentivegna S, Zheng J, Namsaraev E, Carlton VE, Pavlicek A, Moorhead M, Siddiqui F, Wang Z, Lee L, Ireland JS, et al: Rapid identification of somatic mutations in colorectal and breast cancer tissues using mismatch repair detection (MRD). Hum Mutat. 29:441–450. 2008. View Article : Google Scholar : PubMed/NCBI
14	Di Lonardo A, Nasi S and Pulciani S: Cancer: we should not forget the past. J Cancer. 6:29–39. 2015. View Article : Google Scholar : PubMed/NCBI
15	Erstad DJ and Jr JC: Mutational analysis of merkel cell carcinoma. Cancers (Basel). 6:2116–2136. 2014. View Article : Google Scholar
16	Schubert KM and Duronio V: Distinct roles for extracellular-signal-regulated protein kinase (ERK) mitogen-activated protein kinases and phosphatidylinositol 3-kinase in the regulation of Mcl-1 synthesis. Biochem J. 356:473–480. 2001. View Article : Google Scholar : PubMed/NCBI
17	Chao JR, Wang JM, Lee SF, Peng HW, Lin YH, Chou CH, et al: Mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GMCSF) signaling pathway and is one component of the GM-CSF viability response. Mol Cell Biol. 18:4883–4898. 1998.PubMed/NCBI
18	Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F and Wang X: Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 17:1475–1486. 2003. View Article : Google Scholar : PubMed/NCBI
19	Varela I, Tarpey P, Raine K, Huang D, Ong CK, et al: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 469:539–542. 2011. View Article : Google Scholar : PubMed/NCBI
20	Jones S, Wang TL, Shih IM, Mao TL, Nakayama K, et al: Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 330:228–231. 2010. View Article : Google Scholar : PubMed/NCBI
21	Wen PY and Kesari S: Malignant Gliomas in Adults. N Engl J Medicine. 359:492–507. 2008. View Article : Google Scholar
22	Kozopas KM, Yang T, Buchan HL, Zhou P and Craig RW: MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to Bcl-2. Proc Natl Acad Sci USA. 90:3516–3520. 1993. View Article : Google Scholar
23	Day CL, Chen L, Richardson SJ, Harrison PJ, Huang DCS and Hinds MG: Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands. J Biol Chem. 280:4738–4744. 2005. View Article : Google Scholar
24	Clohessy JG, Zhuang J and Brady HJM: Characterisation of Mcl-1 cleavage during apoptosis of haematopoietic cells. Br J Haemato. 125:655–665. 2004. View Article : Google Scholar
25	Domina AM, Smith JH and Craig RW: Myeloid cell leukemia 1 is phosphorylated through two distinct pathways, one associated with extracellular signal regulated kinase activation and the other with G2/M accumulation or protein phosphatase 1/2A inhibition. J Biol Chem. 275:21688–21694. 2000. View Article : Google Scholar : PubMed/NCBI
26	Domina AM, Vrana JA, Gregory MA, Hann SR and Craig RW: MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 23:5301–5315. 2004. View Article : Google Scholar : PubMed/NCBI
27	Zhong Q, Gao W, Du F and Wang X: Mule/ARFBP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 121:1085–1095. 2005. View Article : Google Scholar : PubMed/NCBI
28	Ding Q, Huo L, Yang JY, Xia W, Wei Y, Liao Y, Chang CJ, Yang Y, Lai CC, Lee DF, Yen CJ, Chen YJR, Hsu JM, Kuo HP, Lin CY, Tsai FJ, Li LY, Tsai CH and Hung MC: Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Res. 68:6109–6117. 2008. View Article : Google Scholar : PubMed/NCBI
29	Inoshita S, Takeda K, Hatai T, Terada Y, Sano M, Hata J, Umezawa A and Ichijo H: Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress. J Biol Chem. 277:43730–43734. 2002. View Article : Google Scholar : PubMed/NCBI
30	Morel C, Carlson SM, White FM and Davis RJ: Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis. Mol Cell Biol. 29:3845–3852. 2009. View Article : Google Scholar : PubMed/NCBI
31	Maurer U, Charvet C, Wagman AS, Dejardin E and Green DR: Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of Mcl-1. Mol Cell. 21:749–760. 2006. View Article : Google Scholar : PubMed/NCBI
32	Michels J, Johnson PW and Packham G: Mcl-1. Int J Biochem Cell Biol. 37:267–71. 2005. View Article : Google Scholar
33	Craig RW: Mcl-1 provides a window on the role of the Bcl-2 family in cell proliferation, differentiation and tumorigenesis. Leukemia. 16:444–454. 2002. View Article : Google Scholar : PubMed/NCBI
34	Rinkenberger JL, Horning S, Klocke B, Roth K and Korsmeyer SJ: Mcl-1 deficiency results in periimplantation embryonic lethality. Genes Dev. 14:23–27. 2000.PubMed/NCBI
35	Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC and Korsmeyer SJ: Development and maintenance of B and T lymphocytes requires antiapoptotic Mcl-1. Nature. 426:671–676. 2003. View Article : Google Scholar : PubMed/NCBI
36	Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, et al: Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 19:1294–1305. 2005. View Article : Google Scholar : PubMed/NCBI
37	McDonnell TJ and Korsmeyer SJ: Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature. 349:254–256. 1991. View Article : Google Scholar : PubMed/NCBI
38	Zhou P, Levy NB, Xie H, et al: Mcl-1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood. 97:3902–3909. 2001. View Article : Google Scholar : PubMed/NCBI
39	Townsend KJ, Zhou P, Qian L, et al: Regulation of Mcl-1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the Bcl-2 family to the induction of hematopoietic cell differentiation. J Biol Chem. 274:1801–1813. 1999. View Article : Google Scholar : PubMed/NCBI
40	Thallinger C, Wolschek MF, Maierhofer H, et al: Mcl-1 is a novel therapeutic target for human sarcoma: synergistic inhibition of human sarcoma xenotransplants by a combination of mcl-1 antisense oligonucleotides with low-dose cyclophosphamide. Clin Cancer Res. 10:4185–4191. 2004. View Article : Google Scholar : PubMed/NCBI